Bone alterations of pamidronate therapy in children with cerebral palsy complicating orthopedic management.

Cerebral palsy (CP) is a heterogeneous group of disorders with different clinical types and underlying genetic variants. Children with CP are at risk for fragility fractures secondary to low bone mineral density, and although bisphosphonates are prescribed for the treatment of children with bone fragility, there is limited information on long-term bone impact and safety. Children with CP usually present overtubulated bones, and the thickening of cortical bone by pamidronate treatment can potentially further narrow the medullary canal. Our purpose was to report bone alterations attributable to pamidronate therapy that impact orthopedic care in children with CP. The study consisted of 41 children with CP treated with pamidronate for low bone mineral density from 2006 to 2020. Six children presented unique bone deformities and unusual radiologic features attributed to pamidronate treatment, which affected their orthopedic care. The cases included narrowing of the medullary canal and sclerotic bone, atypical femoral fracture, and heterotopic ossification. Treatment with bisphosphonate reduced the number of fractures from 101 in the pretreatment period to seven in the post-treatment period (P < 0.001). In conclusion, children with CP treated with bisphosphonate have a reduction in low-energy fractures; however, some fractures still happen, and pamidronate treatment can lead to bone alterations including medullary canal narrowing with sclerotic bone and atypical femoral fractures. In very young children, failure to remodel may lead to thin, large femoral shafts with cystic medullary canals. More widespread use of bisphosphonates in children with CP may make these bone alterations more frequent. Level of evidence: Level IV: Case series with post-test outcomes.

Walking status and spinopelvic parameters in young children with achondroplasia: 10-year follow-up.

PURPOSE: Thoracolumbar kyphosis (TLK) is common in children with achondroplasia and resolves in 90% by 10 years of age. Our purpose was to describe the natural progression of TLK in a cohort of pre-walking children with achondroplasia. METHODS: A single-center, retrospective review identified 62 children (32 male, 30 female) with achondroplasia. Clinical information and sagittal spinopelvic parameters were collected. The children were divided into positive pelvic tilt (PT) and negative PT. All parents were routinely counseled about unsupported sitting. RESULTS: Spontaneous resolution rate was 64.5% at 1-year post-walking, 74.2% at 5 years of age, and 88.7% at 10 years of age. None of the children required posterior spinal decompression and fusion for progressive deformity or symptomatic spinal stenosis. At 1-year post-walking, the negative PT group had a higher sacral slope (p = 0.006), higher lumbar lordosis (p < 0.001), and lower pelvic incidence (p < 0.001). This relationship remained constant up to 10 years of age, and there was no association with TLK. CONCLUSION: In this largest series to date, spontaneous resolution of TLK in children with achondroplasia was 64.5% at 1-year post-walking, 74.2% at 5 years of age, and 88.7% in children followed to 10 years of age. With early identification and regular follow-up with patient education, no patient in this series required treatment or developed symptomatic spinal stenosis. While not predictive of resolution of TLK, the dichotomous presentation of PT in young children with achondroplasia persists at 5 and 10 years of age and reliably predicts the spinopelvic parameters. LEVEL OF EVIDENCE: III-retrospective comparative study.

Non-oral manifestations in adults with a clinical and molecularly confirmed diagnosis of periodontal Ehlers-Danlos syndrome.

Introduction: Periodontal Ehlers-Danlos Syndrome (pEDS) is a rare autosomal dominant type of EDS characterised by severe early-onset periodontitis, lack of attached gingiva, pretibial plaques, joint hypermobility and skin hyperextensibility as per the 2017 International EDS Classification. In 2016, deleterious pathogenic heterozygous variants were identified in C1R and C1S, which encode components of the complement system. Materials and Methods: Individuals with a clinical suspicion of pEDS were clinically and molecularly assessed through the National EDS Service in London and Sheffield and in genetic services in Austria, Sweden and Australia. Transmission electron microscopy and fibroblast studies were performed in a small subset of patients. Results: A total of 21 adults from 12 families were clinically and molecularly diagnosed with pEDS, with C1R variants in all families. The age at molecular diagnosis ranged from 21-73 years (mean 45 years), male: female ratio 5:16. Features of easy bruising (90%), pretibial plaques (81%), skin fragility (71%), joint hypermobility (24%) and vocal changes (38%) were identified as well as leukodystrophy in 89% of those imaged. Discussion: This cohort highlights the clinical features of pEDS in adults and contributes several important additional clinical features as well as novel deleterious variants to current knowledge. Hypothetical pathogenic mechanisms which may help to progress understanding and management of pEDS are also discussed.

Managing the "Three Cs" of Academic Literature Authorship: Contributions, Credit, and Conflict.

Dissemination of information through publications is central to academic research, as well as professional advancement. Although seemingly a straightforward endeavor, publication authorship may present challenges. Although the International Committee of Medical Journal Editors defines authorship based on 4 required criteria, contemporary interdisciplinary collaborations can complicate authorship determinations. However, communication that occurs early and frequently in the research and writing process can help to prevent or mitigate potential conflicts, while a process for defining authorship contributions can aid in awarding proper credit. The Contributor Roles Taxonomy (CRediT) defines 14 essential roles of manuscript authors that can be utilized to characterize individual author contributions toward any given publication. This information is useful for academic administrators when evaluating contributors of faculty during promotion and tenure decisions. In the era of collaborative scientific, clinical, and pedagogical scholarship, providing faculty development, including statements of credit in the published work, and developing institutional systems to capture and assess contributions are key.

A Sonography-based Decision Model for Use in Treatment of Developmental Dysplasia of the Hip.

The objective of this study was to delineate a model for management of developmental dysplasia of the hip (DDH) treatment that incorporates hip ultrasound with objective/predicative parameters at key decision-making times. Hip sonograms of 74 infants (59 females, 15 males; 141 hips) with DDH were retrospectively reviewed. Hip sonographic score (HSS; ranges 0-10) was developed to reflect hip status based on sonographic position, stability, and morphology. Analysis on different management groups (i.e., no treatment, successful treatment, and failed treatment) showed that the trend of HSS is helpful in predicting course of the disease and determining effectiveness of treatment. A model for the management of DDH that utilizes an HSS and frequency schedule for hip sonography that is aligned with times of critical treatment decisions is proposed. This model illustrates how hip sonography can bring added value when timed to guide critical treatment decisions. (Journal of Surgical Orthopaedic Advances 32(1):047-054, 2023).

Three different techniques for pelvic fixation in the management of neuromuscular scoliosis in nonambulatory spastic cerebral palsy: A comparative study of Galveston Rod, iliac screw, and sacroiliac screw.

OBJECTIVE: This study aimed to compare the clinical and radiographic results of three different pelvic fixation techniques, i.e., Galveston Rod, Iliac Screw, and Sacroiliac Screw, in managing neuromuscular scoliosis in nonambulatory children with spastic cerebral palsy (CP). METHODS: This retrospective study included nonambulatory children aged < 18 years with neuromuscular scoliosis secondary to CP, undergoing a spinal fusion and pelvic fixation by either Galveston rod, iliac screw, or sacroiliac screw techniques. The primary outcome variable was to determine the stability of the major curve angle and pelvic obliquity over timeline intervals for each pelvic fixation tech nique. The two radiographic parameters were measured at five timeline intervals and were compared to define stability among the groups. RESULTS: One hundred and one patients (54 females [53%]) with spastic nonambulatory CP met the inclusion criteria; the mean age at sur gery was 13.5±3.1 years. Mean follow-up intervals were first-year (12.9±1.5) and second-year (25.8±2.5). Forty-one patients had minimum five-year (81.5±23 months) postoperative follow-up. Groups were based on pelvic fixation techniques: 25 patients with the Galveston rod, 24 with the iliac screw, and 52 with the sacroiliac screw. Of the 41 patients with a minimum five-year follow-up, 10 had the Galveston rod, 11 had an iliac screw, and 20 had sacroiliac screw fixation. Gross Motor Function Classification System level, medical comorbidities, intra thecal baclofen pump, and vitamin D level were compared with each pelvic fixation technique (P > .05). Major curve angle parameters were measured at the five timelines as 70.5°±21.1°, 15.7°±13°, 15.7°±12°, 17.5°±12.7°, and 15.1°±9.6°, and pelvic obliquity as 14.8°±10.4°, 4.9°±4.2°, 5.7°±4.6°, 5°±4.4°, and 7.2°±4.4°, respectively. After the surgery, corrected major curve angle and pelvic obliquity showed no sta tistically significant difference between pelvic fixation techniques (P > .05) and remained stable over timeline intervals (P > .05). Fifteen patients had complications requiring additional surgery. The iliac screw group (nine patients) had the highest rate of complications. CONCLUSION: All three pelvic fixation techniques can provide equivalent correction for major curve angle and pelvic obliquity in managing neuromuscular scoliosis in nonambulatory CP children. Pelvic obliquity after surgery may remain stable regardless of pelvic fixation type. A higher rate of postoperative complication can be encountered with the iliac screw. LEVEL OF EVIDENCE: Level III, Retrospective Study.

Methane emissions and rumen metabolite concentrations in cattle fed two different silages.

In this study, 18 animals were fed two forage-based diets: red clover (RC) and grass silage (GS), in a crossover-design experiment in which methane (CH4) emissions were recorded in respiration chambers. Rumen samples obtained through naso-gastric sampling tubes were analysed by NMR. Methane yield (g/kg DM) was significantly lower from animals fed RC (17.8 ± 3.17) compared to GS (21.2 ± 4.61) p = 0.008. In total 42 metabolites were identified, 6 showing significant differences between diets (acetate, propionate, butyrate, valerate, 3-phenylopropionate, and 2-hydroxyvalerate). Partial least squares discriminant analysis (PLS-DA) was used to assess which metabolites were more important to distinguish between diets and partial least squares (PLS) regressions were used to assess which metabolites were more strongly associated with the variation in CH4 emissions. Acetate, butyrate and propionate along with dimethylamine were important for the distinction between diets according to the PLS-DA results. PLS regression revealed that diet and dry matter intake are key factors to explain CH4 variation when included in the model. Additionally, PLS was conducted within diet, revealing that the association between metabolites and CH4 emissions can be conditioned by diet. These results provide new insights into the methylotrophic methanogenic pathway, confirming that metabolite profiles change according to diet composition, with consequences for CH4 emissions.

Targeting NLRP3 signaling by a novel-designed sulfonylurea compound for inhibition of microglial inflammation.

The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays an important role in microglia-mediated inflammation. Dysregulation of NLRP3 signaling results in microglial activation and triggers inflammatory responses contributing to the development of neurological disorders including ischemic stroke, schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Inhibition of the NLRP3-linked inflammatory pathways reduces microglia-induced inflammation and is considered as a promising therapeutic approach for neuro-inflammatory diseases. In the present study, we report the development of AMS-17, a rationally-designed tertiary sulfonylurea compound for inhibition of inflammation in microglia. AMS-17 inhibited expression of the NLRP3, and its downstream components and cytokines such as caspase-1, tumor necrosis factor-α (TNF-α), IL-1ß and inducible nitric oxide synthase (iNOS). It also suppressed lipopolysaccharide (LPS)-induced N9 microglial cell phagocytosis in vitro and activation of the microglia in mouse brain in vivo. Together, these results provide promising evidences for the inhibitory effects of AMS-17 in inflammation. This proof-of-concept study provides a new chemical scaffold, designed with the aid of pharmacophore modeling, with NLRP3 inhibitory activity which can be further developed for the treatment of inflammation-associated neurological disorders.

The Kynurenine Pathway and Kynurenine 3-Monooxygenase Inhibitors.

Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its production of toxic metabolites that have been implicated in many diseases and disorders. With many of these illnesses having an inadequate or modest treatment, there exists a need to develop KMO inhibitors that reduce the production of these toxic metabolites. Though prior efforts to find an appropriate KMO inhibitor were unpromising, the development of a KMO crystal structure has provided the opportunity for a rational structure-based design in the development of inhibitors. Therefore, the purpose of this review is to describe the kynurenine pathway, the kynurenine 3-monooxygenase enzyme, and KMO inhibitors and their potential candidacy for clinical use.

Worker-fatigue contributing to workplace incidents in New Zealand Forestry.

PROBLEM: Reports of incidents in dangerous work environments can be analysed to identify common hazards, in turn aiding in the prevention of future accidents. Whilst studies exist that do this, most focus on causes that involve physical risks. In this paper we propose an alternative approach, and illustrate causes of forestry incidents from the perspective of worker-failure and fatigue. METHOD: This paper outlines the analysis of eight years' worth of New Zealand forestry incident data, with a focus on the cause of, and time that, incidents occur. RESULTS: This has resulted in two main findings. First, 70% of incidents can be attributed, at least in part, to worker-failures. Second, 78% of worker-failure based causes show indications of fatigue. This indicates that a significant number of forestry incidents are caused by worker-fatigue. Finally, this dataset showed inconsistencies in data quality, similar to those that exist in other datasets. This did not affect our analysis. However, these types of errors have the potential to affect the data quality in the national reporting system. IMPACT ON INDUSTRY: The results from this study will be used in a larger project on detecting fatigue in forestry workers for injury and incident prevention. It is also our hope that other researchers may find these results of interest for further fatigue prevention research in hazardous industries.

The pharmacist in same day emergency care: a service evaluation of pharmacy services on the ambulatory assessment unit at the John Radcliffe Hospital.

Same day emergency care (SDEC) is an increasingly important part of urgent care delivery in secondary care. This service evaluation examined the role of the pharmacy service on a busy SDEC unit over a 3 week period. A total of 634 patients were seen on the unit and 513 pharmacy interventions were made. Patients were taking a mean number of 6.7 medicines and the average age was 59.3. The most common medication type pharmacists intervened in were anticoagulants. To meet the demands of SDEC service, the pharmacy team is crucial for maintaining medication safety and ensuring patient flow through hospital pathways.

Early prediction of respiratory disease in preweaning dairy calves using feeding and activity behaviors.

Bovine respiratory disease (BRD) represents one of the major disease challenges affecting preweaning dairy-bred calves. Previous studies have shown that differences in feeding and activity behaviors exist between healthy and diseased calves affected by BRD. The aim of this study was to develop and assess the accuracy of models designed to predict BRD from feeding and activity behaviors. Feeding and activity behaviors were recorded for 100 male preweaning calves between ~8 to 42 d of age. Calves were group housed with ad libitum access to milk via automatic milk feeders, water, starter diet, and straw. Activity was monitored via a leg-mounted accelerometer. Health status of individual calves was monitored daily using an adapted version of the Wisconsin Scoring System to identify BRD. Three models were created to predict disease: (1) deviation from normal lying time based on moving averages (MA); (2) random forest (RF), a machine learning technique based on feeding and activity variables; and (3) a combination of RF and MA output. For the MA model, lying time was predicted based on behavior over previous days (3- and 7-d MA) and the expected value for the current day (based on calf age; measured using accelerometers). Data were not split into training and test data sets. Occasions when the actual lying time increased >9% of predicted lying time were classified as a deviation from normal and a disease alert was provided. Both feeding and activity behaviors were included within the RF model. Data were split into training (70%) and test (30%) data sets based on disease events. Events were classified as 2 d before, the day(s) of the disease event, and 2 d after the event. Accuracy of models was assessed using sensitivity, specificity, balanced accuracy, and Matthews correlation coefficient (MCC). If a positive disease prediction agreed with an actual disease event within a 3-d rolling window, it was classified as a true positive. Stand-alone models (RF; MA) showed high specificity (0.95; 0.97), moderate sensitivity (0.35; 0.43), balanced accuracy (0.65; 0.64), and MCC (0.25; 0.29). Combining outputs increased accuracy (specificity = 0.95, sensitivity = 0.54, balanced accuracy = 0.75, MCC = 0.36). The work presented is the first to demonstrate the use of modeling data derived from precision livestock farming techniques that monitor feeding and activity behaviors for early detection of BRD in preweaning calves, offering a significant advance in health management of youngstock.

Predicting feed intake using modelling based on feeding behaviour in finishing beef steers.

Current techniques for measuring feed intake in housed cattle are both expensive and time-consuming making them unsuitable for use on commercial farms. Estimates of individual animal intake are required for assessing production efficiency. The aim of this study was to predict individual animal intake using parameters that can be easily obtained on commercial farms including feeding behaviour, liveweight and age. In total, 80 steers were used, and each steer was allocated to one of two diets (40 per diet) which consisted of (g/kg; DM) forage to concentrate ratios of either 494:506 (MIXED) or 80:920 (CONC). Individual daily fresh weight intakes (FWI; kg/day) were recorded for each animal using 32 electronic feeders over a 56-day period, and individual DM intakes (DMI; kg/day) subsequently calculated. Individual feeding behaviour variables were calculated for each day of the measurement period from the electronic feeders and included: total number of visits to the feeder, total time spent at the feeder (TOTFEEDTIME), total time where feed was consumed (TIMEWITHFEED) and average length of time during each visit to the feeder. These feeding behaviour variables were chosen due to ease of obtaining from accelerometers. Four modelling techniques to predict individual animal intake were examined, based on (i) individual animal TOTFEEDTIME relative expressed as a proportion of the dietary group (GRP) and total GRP intake, (ii) multiple linear regression (REG) (iii) random forests (RF) and (iv) support vector regressor (SVR). Each model was used to predict CONC and MIXED diets separately, giving eight prediction models, (i) GRP_CONC, (ii) GRP_MIXED, (iii) REG_CONC, (iv) REG_MIXED, (v) RF_CONC, (vi) RF_MIXED, (vii) SVR_CONC and (viii) SVR_MIXED. Each model was tested on FWI and DMI. Model performance was assessed using repeated measures correlations (R2_RM) to capture the repeated nature of daily intakes compared with standard R2, RMSE and mean absolute error (MAE). REG, RF and SVR models predicted FWI with R2_RM = 0.1-0.36, RMSE = 1.51-2.96 kg and MAE = 1.19-2.49 kg, and DMI with R2_RM = 0.13-0.19, RMSE = 1.15-1.61 kg and MAE = 0.9-1.28 kg. The GRP models predicted FWI with R2_RM = 0.42-0.49, RMSE = 2.76-3.88 kg and MAE = 2.46-3.47 kg, and DMI with R2_RM = 0.32-0.44, RMSE = 0.32-0.44 kg, MAE = 1.55-2.22 kg. Whilst more simplistic GRP models showed higher R2_RM than regression and machine learning techniques, these models had larger errors, likely due to individual feeding patterns not being captured. Although regression and machine learning techniques produced lower errors associated with individual intakes, overall precision of prediction was too low for practical use.

Dopamine and the interdependency of time perception and reward.

Time is a fundamental dimension of our perception of the world and is therefore of critical importance to the organization of human behavior. A corpus of work - including recent optogenetic evidence - implicates striatal dopamine as a crucial factor influencing the perception of time. Another stream of literature implicates dopamine in reward and motivation processes. However, these two domains of research have remained largely separated, despite neurobiological overlap and the apothegmatic notion that "time flies when you're having fun". This article constitutes a review of the literature linking time perception and reward, including neurobiological and behavioral studies. Together, these provide compelling support for the idea that time perception and reward processing interact via a common dopaminergic mechanism.

Feeding behaviour and activity as early indicators of disease in pre-weaned dairy calves.

Across the industry, there is large variation in health status of dairy calves and as a result, disease incidence and antibiotic use is high. This has significant implications for animal welfare, productivity and profitability of dairy and dairy-beef production systems. Technology-based early detection systems could alleviate these issues; however, methods of early detection of disease in dairy calves have not been widely explored. This study aimed to determine whether changes in activity and feeding behaviour can be used as early warning indicators of respiratory disease in calves. In total, 100 pre-weaned male Holstein calves (age: ~8-42 days) were used. Calves were group-housed and provided with starter diet, straw bedding and ad libitum water. Calves were fed milk replacer ad libitum through an automatic calf feeder, and each calf was fitted with a leg-mounted activity monitor. Daily activity and feeding behaviour variables were calculated for each calf. Each calf was assessed daily using a modified version of the Wisconsin Scoring System to assess respiratory disease status. Calves were classed as 'Diseased', 'Intermediate' or 'Healthy' based on their cumulative health score. The peak day of the most extreme illness event was identified for each calf. Data from Diseased and Healthy calves were paired for analysis based on age and BW. Data were compared for the day of peak illness, and for the 3 days previous and post. Compared to healthy calves, diseased calves lay for longer and tended to have longer lying bouts (daily lying: 17.6 ±â€¯0.3 vs 16.7 ±â€¯0.2 h, P < 0.01; bout length: 74.8 ±â€¯10.6 vs 56.0 ±â€¯3.7 min, P = 0.09 for diseased and healthy calves, respectively). Diseased calves fed for a shorter time and had fewer feeder visits (with intake) each day compared to healthy calves (feeding time (min): 19.3 ±â€¯1.4 vs 22.8 ±â€¯1.5; P < 0.05; visits: 2.1 ±â€¯0.2 vs 3.2 ±â€¯0.4; P < 0.05). Importantly, differences between diseased and healthy calves were evident in both activity and feeding behaviour on the days prior to the peak day of disease. Lying bout length was greater in diseased calves for the 2 days prior to the peak day (P < 0.05), lying time was longer on day -1 (P < 0.05) and feeder visits with milk intake were less frequent on day -3 (P < 0.05). Thus, measurement of feeding and activity using precision technology within early detection systems could facilitate early intervention and optimized treatment.

Mentalizing During Social Interaction: The Development and Validation of the Interactive Mentalizing Questionnaire.

Studies have shown that during social interaction a shared system underlies inferring one's own mental state, and the mental states of others - processes often referred to as mentalization. However, no validated assessment has been developed to measure second order mentalization (one's beliefs about how transparent one's thoughts are to others), or whether this capacity plays a significant role in social interaction. The current work presents a interactive mentalization theory, which divides these directional and second order aspects of mentalization, and investigates whether these constructs are measurable, stable, and meaningful in social interactions. We developed a 20-item, self-report interactive mentalization questionnaire (IMQ) in order to assess the different sub-components of mentalization: self-self, self-other, and other-self mentalization (Study 1). We then tested this scale on a large, online sample, and report convergent and discriminant validity in the form of correlations with other measures (Study 2), as well as correlations with social deception behaviors in real online interaction with Mturk studies (Study 3 and Study 4). These results validate the IMQ, and support the idea that these three factors can predict mentalization in social interaction.

The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

Infantile Tibia Vara (Blount Disease) with Iatrogenic Changes Causing Residual Tibial Deformities.

Treatment of infantile tibia vara or Blount disease (ITV/BD) in patients < 3 years old and Langenskiold stages I-III consists of orthosis and, in relapsing cases, proximal tibial osteotomy and/or proximal tibial guided growth laterally with a tension band plate. Our aim was to evaluate the results of treatments in a consecutive group. After Institutional Review Board approval, data from 2002 to 2018 were collected. Thirty-nine knees (average age 22.4 months) with ITV/BD were treated with orthoses, and 10 knees failed. Six knees showed hyperintense T2-weighted signal in the medial proximal tibial epiphyseal cartilage on magnetic resonance imaging. Three of six knees with tibial osteotomy failed and underwent guided growth. Tibial plateau slopes were abnormal medially from the ITV/BD and laterally from the guided growth (triangular physis and depressed plateau deformities) because of factors such as orthotic treatment, tibial osteotomy, magnetic resonance imaging "physis severity score," and guided growth. (Journal of Surgical Orthopaedic Advances 29(3):141-148, 2020).

Prediction of mucositis risk secondary to cancer therapy: a systematic review of current evidence and call to action.

PURPOSE: Despite advances in personalizing the efficacy of cancer therapy, our ability to identify patients at risk of severe treatment side effects and provide individualized supportive care is limited. This is particularly the case for mucositis (oral and gastrointestinal), with no comprehensive risk evaluation strategies to identify high-risk patients. We, the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) Mucositis Study Group, therefore aimed to systematically review current evidence on that factors that influence mucositis risk to provide a foundation upon which future risk prediction studies can be based. METHODS: We identified 11,018 papers from PubMed and Web of Science, with 197 records extracted for full review and 113 meeting final eligibility criteria. Data were then synthesized into tables to highlight the level of evidence for each risk predictor. RESULTS: The strongest level of evidence supported dosimetric parameters as key predictors of mucositis risk. Genetic variants in drug-metabolizing pathways, immune signaling, and cell injury/repair mechanisms were also identified to impact mucositis risk. Factors relating to the individual were variably linked to mucositis outcomes, although female sex and smoking status showed some association with mucositis risk. CONCLUSION: Mucositis risk reflects the complex interplay between the host, tumor microenvironment, and treatment specifications, yet the large majority of studies rely on hypothesis-driven, single-candidate approaches. For significant advances in the provision of personalized supportive care, coordinated research efforts with robust multiplexed approaches are strongly advised.

Design, synthesis, and screening of sulfonylurea-derived NLRP3 inflammasome inhibitors.

Inflammasomes are multiprotein assemblies that produce robust inflammatory responses upon stimulation with pathogen- and/or danger-associated molecular patterns. Uncontrolled inflammasome activation has been linked to the pathophysiology of a wide array of disorders including life-threatening pathogenic infections, e.g., Francisella tularensis. There has been a great deal of interest in the development of small molecule inflammasome inhibitors. Using computational modeling based on chalcone derivatives, we have developed novel tertiary sulfonylurea compounds as inhibitors of the NLRP3 inflammasome. The polar enone functional alert of chalcone was replaced with a sulfonylurea scaffold while maintaining the relative positions of the two aromatic rings. These compounds were evaluated for their ability to inhibit NLRP3 and AIM2 inflammasome activation triggered by Francisella tularensis infection.